Process for preparing them



l atentecl Jan. 10, 195

UNITED STATES TEN BARBITURIC ACID DERIVATIVES AND PROCESS FOR PREPARING THEM William F. Bruce, Havertown, Pa., George -Muel-- ler, Knoxville, Tenn, and Joseph Seiften-Willow Grove, and Joseph Lester SzabmDrexel Hill, Pa., assignors to Wyeth Incorporated, Philadelphia, Pa., a corporation of Delaware No Drawing. Application J une28 194 7 Serial No. 757,922

13 Claims. (Cl. v260-4557) Ill The compounds made in accordance with the disclosed methods may be represented by the structural formula:

Where R is an alkyl radical of 2- to 5 carbon atoms, an alicyclic radical of 3 to 5 carbon atoms, an alicyclicalkyl radical of 4 to 5 carbon atoms, or an alkenyl radical having 3 to 5 carbon atoms, R1 is H or an alkyl radical of 1 to 2 carbon atoms, X represents 0 or S and Y represents a member of the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, or in fact, any salt of an organic base such as alkyl ammonium or dialkyl ammonium.

' The new compounds of the invention are'useful pharmacologically as anesthetics, sedatives, anticonvulsants, soporifics and hypnotics, some of these displaying a relatively fast action of comparative short duration while others possess an action of relatively long duration, which properties render the new compounds suitable for specific therapeutic purposes.

In accordance with the present invention, the new barbituric or thiobarbituric acids are obtain able by reducing methyl cyclopropyl ketone to form l-cyclopropyl-ethanol-l. The latter product is treated with a suitable halide to form 1- cyclopropyl l-halo-ethane which is then reacted with a suitable alkali metal malonic ester as represented by the general formula:

00002115 RC/ ooooin alkali metal to form OH-CH-O COOCzH;

, .2 where R represents the radicals indicated hereinabove. .This product is then condensed with urea, guanidine, thiourea or the mono-N-alkylated derivatives ofthese to form-the 5-alphacyclopropylethyl 5 -alkyl, alicycllc, alicyclicalkyl or .-alkenyl barbituric or thiobarbituric acid derivatives. r

The first reductionstepiof methylcyclopropyl ketone to form' thealcohol is carried out either by a hydrogenation in the presence of a suitable hydrogenation catalyst; or by-reducing said ketone with aluminumlsopropoxide .in, the presence of isopropyl alcohol. A reduction wherein hydrogen is formed in situ, as for example, by the use of sodium in the-presence of ethanol, has been found to give low yields due to unavoidable openingof the alicycli'c -ring. It has been found that while known hydrogenation catalysts are in general operable, the yields vary depending on the catalysts selected. For example, both nickel and palladium will reduce the ketone but the yields are relativelylow due to the fact that the alicyclic ring is opened to a considerable extent. On the other hand, excellent results have been obtained with platinum catalysts. The hydrogenation is carried out at about room temperature and at a pressure ofaboutGO p. s i. initially. The reaction is, of course, exothermic and the temperature is permitted to rise .while the pressure during the reaction may'range from the initial pressure to about 10 p. s. i. r 1 5 a Following the reduction of the ketone to cyclopropylethanol,- the hydroxy radical is replaced by a halogen, the, alcohol being treated with dry hydrogen halide such as hydrogen chloride, hydrogen bromideor hydrogen iodide; or with thionyl chloride; or with hydrogen chloride or bromide in the presence of sulfuricacid or zinc chloride; or with-phosphorous tr i-or pentachloride. It has been noted that when HBr is used, the operation is best carried out at a temperature of 50 to 80 C. in order to avoid opening the ring. At higher temperatures, such as 0 C., the alicyclic ringis opened and the yields are-correspondinglyq low. The preferred halide in all cases is the chloride and the preferred reagent is dry hydrogen chloride which'has been found to give the best results since the reaction is not influenced by the temperature of operation which may range from C. to 25 C.

The halide product produced in the above step is then reacted with the 'diethyl ester of the alkali metal derivative of the alkyl, alicyclic, alicyclicalkyl. or alkenyl substituted malonic acid, in the presence of a suitable solvent. It has been T 1 0mm 1 found that while polar or non-polar solvents may be used, the yield of the desired product varies in accordance with the solvent selected. Thus, the non-polar solvents such as benzene and toluene and the polar solvent such as diethyl ether give high yields while ethyl alcohol as a solvent has been found to give low yields due to side reactions. The preferred solvent for this reaction is benzene. The resulting product as stated before is then condensed with urea, guanidine, thiourea or the mono-N-alkylated derivatives of these, depending on the product desired.

The invention is further illustrated by the following examples but it is to be understood that these examples are not to be considered limitative of the invention.

EXAMPLEI Reduction of methyl cyclopropyl keto ne to methyl cyclopropyl earbinol, method No. 1

Methyl cyclopropyl ketone (42 grams) was reduced with hydrogen in the presence of-0.4 gram of platinum oxide at room temperature and under 60 lbs. per square inch hydrogen pressure. After about 4.5 hours, the reaction products were removed and filtered to separate out the catalyst. On distillation, methyl cyclopropyl carbinol was collected at 121-122 C.'; n ?=l.4305.

EXAMPLE II Reduction of methyl cyclopropyl ketone to methyl cyclopropyl carbz'nol, method No. 2

To 1800 cc. isopropanol, which had been dried and distilled over calcium oxide, 81 g. aluminum and 15 g. mercuric chloride were added. e mixture was heated until reaction began and then heat removed until the rate of reflux became constant; and was heated under reflux for 21 hrs. Th reaction flask was then fitted with a modified Hahn condenser so arranged as to have a water condenser at the top and a downward water condenser at the side arm. A 60-40 mixture of isopropanol-acetone was added to the inner tube of the Hahn condenser. 252 g. (3 m.) methyl cyclopropyl ketone was added dropwise and the temperature of the reaction held ata point to maintain a rate of distillation of one drop every 1 /2 to 2 minutes. The distillation was continued until test for acetone was negative, or about 62 hours. The mixture was'then chilled in an ice bath and acidified with 450 g. H2504 in 2 kg. chopped ice, The oily layer was separated and the aqueous layer was extracted three times with ether. The ether and oily layers were combined and washed with saturated NaCl solution, dried over Na2SO4; filtered and concentrated. The fractionated product boiled at 121-123", n =l.4315.

The alcohol obtained from either catalytic reduction or aluminum isopropoxide reduction of methyl cyclopropyl ketone was found to yield the N-phenylcarbonate melting at 70-71? C. (Bellstein, 70 0.); Analysis: N, calculated 6.83; found, 6.70. EXAMPLE III Preparation of 1 -cyclopropylethyl halides To grams of l-cyclopropylethanol-l cooled to ,80 (3., approximately 3 cc. of liquid hydrogen bromide was added. After standing in a Drylcebath overnight, the product containing some water from the reaction was distilled directly. On redistillation of appropriate fractions,

l-cyclopropyl-l-bromoethane was obtained which boiled at 57-58 C. at a pressure of '70 mm; 11. 1.4702;

dig 1.2818

Bromine, calculated 53.5 found, 53.3.

"To 5 grams of l-cyclopropylethanol-l there was added 0.62 gram of red phosphorus (washed with water, alcohol and dried at 100 C. in vaciodine was added in small portions.

uum). To this mixture, 7.3 grams of powdered After the addition, the product was distilled, obtaining a fraction boiling at 38-39 C. at a pressure of 8 mm. This fraction was placed in the refrigerator over mercury until colorless and was again distilled, yielding 1 -cyclopropyll-iodoethane boiling residue fractionated; Boilingpoint 46.5 C. at a pressure of 12 mm., 11. 1.5226.

For the preparation of the chloride, l-cyclo pro pylethanol-l (0.2 mol) was cooled'ina'n icez-bathand a rapid stream of hydrogen chloride gaswaspassed through it. The alcoholrapidly became turbid due to the separation of water and the.

absorption of hydrogen chloridebecame slower. When complete saturation had been reached, two

. layers formed. The lower acid layer was removed and the organic layer was washed well with ice water, dried over calcium chloride and distilled. The desired fraction of l-cyclopropyl-l-chloroethane boiled at 104.5" C. at a pressure of 767 mm., n 1.4322,

EXAMPLE IV Preparation of diethyl cyclopropylmethylcarbinyl-allylmalonate In a3-necked ml. flask, 2.3 grams of, sodium was dissolved in 30v cc. of absolutealcohol and 0.1 mol (20 grams) of diethyl-allylmalonatewas added. This wasfollowed by 15. 7 'g. of l-cycloprcpyl-l-bromoethane. Heatin and stirring were continued for onehou-r, afterwhich a large proportion of the alcohol was distilled in vacuo.-

The-residue was washedwith water, neutralized; dried, and. distilled. The diethyi' cyclopropylmethylcarbinyl allylmalonate boiled from 129-1- 132 C. at a pressure of' 4.8 mm.; n 1.4528. Analysis: calculatedfor 'CisHz4OiC, 67.13, H, 9.02; found: C, 67.05,H, 8.91.

EX MPLE v Preparation of diethyl cyclopropillmethyloar biaylethyZ-muloaate The sodium chloride was.

a ane t'ralized', concentrated in vacuo anddistilledt Thez.

product boiled at 104-8 C. at 2.5 mm. n -l.='.44'5'5; (131.0140

The above reaction proceedssimilarly whenusing. the bromide instead of the chloride and although...

benzene is preferred as a solvent, other non-polar solvents such as toluene maybe substituted there: for. if desired. Among the polar solvents, ethyl. ether has also been found useful.

Preparation of 5-cyclopropylmethylcarbinyl-S alZyZ-barbiturz'c acid Using oven-dried glassware and ethanol rendered absolute over sodium andethyl phthalate, a solution of sodium ethylate was prepared by dissolving 1.35 g. (0.0586 mol) of clean sodium metal in 30 cc. of alcohol. The reaction was protected from moisture by a calcium chloride tube. Diethyl cyclopropylmethylcarbinyl allyl maloenate, 7.85 g. (0.0293mol), and dried, powdered urea, 1192 g. (0.032 mol) Were then addedand'dissolved by brief shaking. The reaction mixture was heated on the steam bath; a fiocculent precipitate began to appear after minutes; Heat ing was continued during hours. The alcohol solvent was removed in vacuo while continuing the heating and the dry residue cooled and dissolved in cc. of water. An undissolved oily substance was present. This was removed by washing the aqueous layer with four 20 cc. portions of ether. The aqueous layer was evacuated to remove dissolved ether and acidified with acetic acid. The precipitated gum was collected in four 20 cc. portions of ether and. this solution. dried. and evaporated. The crude oil was precipitated. from dry-ether solution as a sodium salt bythe. calculated quantity of sodium ethylate in alcohol,v and this was in turn dissolved in water, dilute hy.--

drochloric acid being added to liberate the free barbituric acid, which crystallized on standing. The product was recrystallized from ether-hex ane mixtures, melting initially at 73.5-82 C. and after a third recrystallization at 80.0-87.0 C.

Analysis: calculated for CizHmOsNz-C, 61.00; H, 6.83; N, 11.86. Found: C, 61.14; H, 6.70; N, 11.36; 11.42.

EXAMPLE VII Preparation of" 5cyclopropy-Zmethylca'rbinyl-5 ethyl barbituric acid 1:28gramsof' the malonateester, (diethyl cyc.lo -.v propylmethylcarbinyl ethylmalonate.) and: 6.0; grams of urea are added to .asolution of 34.5. grams oisodium in 900 cc. of dry isopropyl alcohol. and

refluxed for 48 hours. The products were-cooled;

trated HCl with cooling to apH of about- 8: At this point a solid precipitate is gradually depos ited and is left standing in ice for further precipitation. The precipitate is collected and driedproducing a second-filtrate. The barbituric acid s;

had a melting-pointer 161-163.*'C.. (uncorrectedle.

The second filtrate is acidified further to.-'pH:'6s and: further quantity of less pure barbituric acidawasc obtained; On recrystallization from aminimum. amount-of eth-y-l acetate and hexane,,the bar-b bituric acid compound gave a melting point-of? 164 C; rectedb Analysis: calculated for C11H1603N2+-C 58292,.

(uncorrected) and 166-4665? C; (cor I-1; 7.14; N', 12.50; Foundi C, 58.61; H, 7.46;

This'5-ethyl barbituric acid is anisomer ofthe S-ethyl' barbituric acid produced in accordance with the method disclosed in co-pending application Ser. No. 717,806 of Opie et al.

EXAMPLE VIII.

Preparation of 5 -alphacgclopropylethyl-5 n. propyl-barbitaric. acid A solution of 1.55 grams of B-alpha-cyclopropylethyl-5-allyl-barbituric acid melting at 142- 144 C., in 10 cc. of methanol with 0.1 gram of patinum oxide was shaken with hydrogen at atmospheric pressure. The theoretical amount. of; hydrogen.(168 cc.) required bythe organic;ma.-. terial-splus that required by the catalyst (22 cc.)- was absorbed in 35 minutes after which little. if; any; further absorption occurred. The. catalyst;

2 was; filtered out; thefiltrate was concentrated in vacuo on a. water bath. The glassy 00101185511651- duewasztaken up in-hexane containing 5% ethyl acetate. On standing; crystals appearedmelting.

at. -113" C. On recrystallization from 50%.: methanol, and drying over acetone and then. was ter in a Fischer pistol, the product melted sharp- EXAMPLE IX Preparation of 5-alpha-cyclopropylethyl-5-ethyl" thiobarbituric acid and its sodium, salt uct melted at 126-8 C. Upon recrystallization" twice from 10% methanol in water, it melted at -6 C. From the filtrate of the original=re=- actionmixture on concentration ina vacuum and addition of 10 cc. of 10% sodium hydroxide 4.5-

grams of unchanged ester was extracted from the alkaline mixture. The aqueous solution on acidification and extraction with ether gave 3 grams of oil which crystallized on addition of etherpetroleum ether to give the same compoundabove described.

Analysis: calculatedfor C11H16N202SN, 11.66; S, 13.34. Found N, 11.70; 8, 13.64.

EXAMPLE X Preparation. of. 5,-ally1-S-aZpha-cyclopropalethyl thiobarbitaric acid diethyl cyclopropylmethylcarbinyr-allylemalonates (as prepared in Example IV). The solid which formed was collected on a filter. The filtrate was.

concentrated in vacuo; the residue dissolved in a small amount of water and the water was extracted repeatedly by ether to remove unchanged malonate. The water solution was acidified and extracted repeatedly with ether. The ether solution was distilled to evaporate the ether and an oil was obtained. This was dissolved in an; equal volume of ethyl acetate and hexane (66-68? C.)

was added to incipient cloudiness. On standing, crystals of -allyl-B-alpha-cyclopropylethyl-thiobarbituric acid were obtained which, after four crystallizations from the same solvents, melted at 139 C.

Analysis: calculated for C12H1sN2O2SC, 57.15; H, 6.39; N, 11.12; 8,1271. Found: C, 57.37; H, 6.47; N, 11.18; S, 12.73.

EXAMPLE 2H barbituric and thz'obarbz'turic acid salts 'I'he salts of the new barbituric and thiobarbituric acid derivatives are obtained by neutraliz- Preparatzon of the ing with bases in the well-known manner, as for 7 example, with alkali metal hydroxide or alcoholate, alkaline earth metal hydroxide or alcoholate, an aqueous or alcoholic solution of concentrated ammonia or with an alkylamine such as methyl or ethyl amine or with a dialkyl amine such as dimethylor diethylamine. cedure illustrates the formation of the sodium salt. Other salts may be prepared in the same manner as illustrated in co-pending application, Ser. No. 717,806 of Qpie et al.

Sodium salt: one gram of S-cyclopropylmethylcarbinyl-5-allylbarbituric acid was dissolved in 2.5 cc. (0.00423 moi) of a sodium ethyla-te solution and the sodium salt was then precipitated by the addition of anhydrous ether. The precipitatewas white and flufiy, the yield being 96%.

of theoretical.

We claim:

1. A barbituric compound represented by the general following formula in which alkenyl in the formula represents an alkenyl radical having from 3 to 5 carbon atoms, Where R is a member of the group consisting of hydrogen and an alkyl having 1 to 2 carbon atoms in the molecule, X is a member of the in which alkenyl in the formula represents an alkenyl radical havin from 3 to 5 carbon atoms, where R is a member of the group consisting of hydrogen and an alkyl having 1 to 2 carbon atoms in the molecule and Y represents a member of the group consisting of hydrogen, an alkali metal,

The following pro-.

8 an alkaline earth metal, ammonium, alkylam monium and dialkylammonium.

3. A barbituric compound represented by the formula 0E2 CH3 1 c-ztn C0-N-R CH: /C 1:3:8 alkenyl O-NY in which alkenyl in the formula represents an alkenyl radical having from 3 to 5 carbon atoms, where R is a member of the group consisting of hydrogen and an alkyl having 1 to 2 carbon atoms in the molecule; and Y represents a member of i the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

4. A barbituric compound represented by the in which alkenyl in the formula represents an alkenyl radical having from 3 to 5 carbon atoms,

where X is a member of the group consisting of O and S and Y represents a member of the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

5. A barbituric compound represented by the formula where R is a member of the group consisting of hydrogen and an alkyl having 1 to 2 carbon atoms in the molecule, X is a member of the group consisting of O and S; and Y represents a member of the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

6. A barbituric compound represented by the formula where R is a member of the group consisting of hydrogen and an alkyl having 1 to 2 carbon atoms in the molecule and Y represents a member of the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

7. A barbituric compound represented by the formula 0H, CH:

l2.- re:

allyl O-N-Y where R is a member of the group consisting of hydrogen and an alkyl having 1 to 2 carbon atoms in the molecule; and Y represents a member of the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

8. A barbituric compound represented by the formula where X is a member of the group consisting of O and S and Y represents a member of the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

9. Sodium 5-alpha cyclopropylethyl 5 allyl barbiturate.

10. In the process of preparing a 5-alicyclicalkyl- 5-substituted barbituric acid, the steps comprising reducing an alicyclicalkyl ketone to form the corresponding alcohol, reacting the latter compound with a, halide to form an alicyclic alkyl halide and alkylating a malonic ester with said halide to form a substituted malonic ester.

11. The process of claim 10, wherein the re- REFERENCES CITED Thefollowing references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Shonle Nov. 5, 1935 OTHER REFERENCES Chemical Abstracts 32, 2912 (1938).

Number. 

1. A BARBITURIC COMPOUND REPRESENTED BY THE GENERAL FOLLOWING FORMULA 